This R34 application responds to PAR-09-173, to achieve the first goal of this FOA by supporting: "the development and/or pilot testing of new or adapted interventions." The two overarching goals of this application are: 1) to test the effects of the acute administration of the NMDA antagonist, memantine (MEM), on sensorimotor gating and working memory (WM) in schizophrenia (SZ) patients, and 2) to assess the feasibility of using MEM to predictably enhance the therapeutic benefits of cognitive training in SZ. The pharmacotherapy of SZ has been dominated by antidopaminergic drugs with limited clinical impact. Some forms of psychosocial rehabilitation, such as cognitive training (CT), appear to effectively reduce symptoms and improve function in SZ. The premise of this application is that the benefits of CT in SZ might be enhanced by drugs that increase specific cognitive abilities, including WM, even if these pro-cognitive drugs lack clinical impact when administered without CT. The main goal of this application is to develop an innovative intervention strategy that enhances the clinical benefits of CT in SZ through administration of a pro-cognitive agent to biomarker-identified sensitive patients. We reported that a single dose of the widely used Alzheimer's disease medication, MEM (20 mg p.o.), significantly increased prepulse inhibition (PPI) of the startle reflex in healthy subjects. PPI-enhancing effects of MEM in healthy subjects are associated with: 1) increased WM;and 2) phenotypes linked to the high activity Val158Met COMT polymorphism. PPI is consistently impaired in SZ patients;lowest levels of PPI in patients are associated with: 1) poor functional outcome;and 2) the Val/Val COMT genotype. If our MEM findings in healthy subjects are reproduced in SZ patients, we will detect MEM-associated improvements in PPI and WM, particularly among Val/Val patients. We will then be positioned to test the hypothesis that acute PPI and WM- enhancing effects of MEM predict therapeutic benefit of MEM in SZ patients undergoing CT. This application has two aims:
Aim 1 will assess the acute effects of MEM (0 vs. 10 or 0 vs. 20 mg p.o.) in 60 SZ patients, to test the prediction that MEM will increase PPI and enhance WM in SZ patients, particularly in those characterized by low basal PPI levels and/or the Val/Val COMT genotype. Mismatch negativity and gamma band synchronization will also be assessed as potentially informative MEM-sensitive and functionally relevant biomarkers.
Aim 2 will assess the feasibility of testing the therapeutic benefit of MEM as an adjunct to CT in SZ patients, and the feasibility of testing the primary hypothesis that such benefit will be predicted by increased PPI and/or WM in SZ patients after the Aim 1 single dose MEM challenge. It is predicted that subject recruitment and completion in both arms of a controlled 12-week CT trial in SZ out- patients among subjects completing Aim 1 will be appropriate for testing both the overall effectiveness of MEM as an adjunct to CT and the ability to predict this effectiveness among biomarker-identified patient subgroups.

Public Health Relevance

Cognitive training is moderately effective at reducing symptoms and improving life function in schizophrenia patients. The present application develops a strategy for increasing the effectiveness of cognitive training through the use of pro-cognitive medications. Specific biomarkers will be studied that identify patients most sensitive to these pro-cognitive medications, to test the feasibility of using these biomarkers in a large clinical trial of medication-enhanced cognitive training in schizophrenia.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Planning Grant (R34)
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Interventions Committee for Adult Disorders (ITVA)
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Hillefors, MI
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Rissling, Anthony J; Miyakoshi, Makoto; Sugar, Catherine A et al. (2014) Cortical substrates and functional correlates of auditory deviance processing deficits in schizophrenia. Neuroimage Clin 6:424-37
Swerdlow, Neal R; Hines, Samantha R; Herrera, Sebastian D et al. (2013) Opposite effects of tolcapone on amphetamine-disrupted startle gating in low vs. high COMT-expressing rat strains. Pharmacol Biochem Behav 106:128-31
Chou, Hsun-Hua; Talledo, Jo A; Lamb, Sarah N et al. (2013) Amphetamine effects on MATRICS Consensus Cognitive Battery performance in healthy adults. Psychopharmacology (Berl) 227:165-76
Swerdlow, Neal R (2012) Beyond antipsychotics: pharmacologically-augmented cognitive therapies (PACTs) for schizophrenia. Neuropsychopharmacology 37:310-1